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  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/50—Pyridazines; Hydrogenated pyridazines
  • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
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  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
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  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems

Definitions

• the present invention relates to substituted bicyclic heterocyclic compounds useful as DDR1 kinase inhibitors and pharmaceuticals containing such compounds.
• Discoidin Domain Receptor 1 (also called DDR1) is a tyrosine kinase receptor belonging to the discoidin domain receptor family and is known to be involved in cell proliferation and differentiation as well as migration, invasion and adhesion. It is mainly expressed on epithelial cells in the lung, kidney, mammary gland, gastrointestinal tract, and the like.
• Activation of DDR1 is involved in various renal diseases.
• it is involved in the pathological conditions of renal diseases, including Alport syndrome, which is caused by mutations in the type IV collagen gene (see Non-Patent Documents 1 and 2), IgA nephropathy (see Non-Patent Document 3), Goodpasture syndrome (see Non-Patent Document 4), lupus nephritis (see Non-Patent Document 4), ANCA (anti-neutrophil cytoplasmic antibody) related nephritis (see Non-Patent Document 5), diabetic nephropathy (see Non-Patent Document 6), and the like.
• Alport syndrome which is caused by mutations in the type IV collagen gene (see Non-Patent Documents 1 and 2), IgA nephropathy (see Non-Patent Document 3), Goodpasture syndrome (see Non-Patent Document 4), lupus nephritis (see Non-Patent Document 4), ANCA (anti-
• Non-Patent Document 7 Activation of DDR1 has also been reported to be involved in various fibrotic diseases, including pulmonary fibrosis (see Non-Patent Document 7) and liver cirrhosis (see Non-Patent Document 8).
• DDR1 has been reported to be involved in the function of Th17 cells involved in autoimmune diseases or allergies (see Non-Patent Document 9).
• Th17 cells are involved in the pathogenesis of diseases such as rheumatoid arthritis, multiple sclerosis, ulcerative colitis and Crohn's disease.
• DDR1 has also been reported to be involved in cancer-related pathogenesis, for example, that of acute myeloid leukemia (see Non-Patent Document 10), acute lymphoid leukemia (see Non-Patent Document 11), chronic lymphocytic leukemia (see Non-Patent Document 12), Hodgkin lymphoma (see Non-Patent Document 13), glioma (see Non-Patent Document 14), non-small-cell lung cancer (see Non-Patent Document 15), breast cancer (see Non-Patent Document 16), ovarian cancer (see Non-Patent Document 17), prostate cancer (see Non-Patent Document 18), colorectal cancer (see Non-Patent Document 19), and the like.
• acute myeloid leukemia see Non-Patent Document 10
• acute lymphoid leukemia see Non-Patent Document 11
• chronic lymphocytic leukemia see Non-Patent Document 12
• Hodgkin lymphoma see Non-Patent
• DDR1 has been reported to be involved in other pathological conditions such as systemic lupus erythematosus (see Non-Patent Document 5), osteoarthritis (see Non-Patent Document 20), heparin-induced thrombocytopenia (see Non-Patent Document 21), atherosclerosis (see Non-Patent Document 22) and vitiligo vulgaris (see Non-Patent Document 23).
• DDR1 inhibitors may provide a new treatment for these DDR1-related diseases.
• the object of the present invention is to provide a compound having DDR1 kinase inhibitory activity, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
• the present inventors have found that the compounds described below or pharmaceutically acceptable salts or solvates thereof have excellent DDR1 kinase inhibitory activity, and thus have completed the present invention.
• the present invention includes the following embodiments (Item 1) to (Item 22).
• R 1 s are each independently selected from the group consisting of hydrogen, halogen, oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, amino, monoalkylamino, dialkylamino, aminoalkyl, alkylcarbonylamino, C 3 -C 10 cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, each of which may be optionally substituted, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
• R 4 is selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, hydroxy, carboxy, alkylcarbonyloxy, amino, monoalkylamino, dialkylamino, aminoalkyl, alkylcarbonylamino, C 3 -C 10 cycloalkyl, C 3 -C 6 cycloalkenyl, heterocycloalkyl, aryl, and heteroaryl, each of which may be optionally substituted, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
• a pharmaceutical composition comprising the compound according to any one of Items 1 to 15, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
• a DDR1 kinase inhibitor comprising the compound according to any one of Items 1 to 15, or a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient.
• a prophylactic agent or therapeutic agent for Alport syndrome IgA nephropathy, Goodpasture syndrome, anti-glomerular basement membrane nephritis, lupus nephritis, ANCA-related nephritis, diabetic nephropathy, purpura nephritis, focal segmental glomerulosclerosis, chronic kidney failure, minimal change nephrotic syndrome, mesangial proliferative glomerulonephritis, membranoproliferative glomerulonephritis, crescentic glomerulonephritis, membranous nephropathy, pulmonary fibrosis, myelofibrosis, liver fibrosis, acute myeloid leukemia, chronic myelogenous leukemia, acute lymphoid leukemia, chronic lymphocytic leuk
• Alkenyl as used herein includes, for example, a straight or branched alkenyl having 1 or 2 double bonds and 2 to 8 carbon atoms (C 2 -C 8 ). Specific examples thereof include ethenyl, 1-propenyl, 2-propenyl, 1-methyl-2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-4-pentenyl, and the like.
• a preferred example is an alkenyl having 2 to 6 carbon atoms, and a more preferred example is an alkenyl having 2 to 4 carbon atoms.
• Alkynyl as used herein includes, for example, a straight or branched alkynyl having 1 or 2 triple bonds and 2 to 8 carbon atoms (C 2 -C 8 ). Specific examples thereof include ethynyl, 1-propynyl, 2-propynyl, 1-methyl-2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-4-pentynyl, and the like.
• a preferred example is an alkynyl having 2 to 6 carbon atoms, and a more preferred example is an alkynyl having 2 to 4 carbon atoms.
• alkyl part in “alkylcarbonyl”, “monoalkylamino”, “dialkylamino”, and “aminoalkyl” as used herein includes, the same examples as the above “alkyl”.
• Haloalkyl as used herein includes, for example, the above “alkyl” wherein 1 to 3 hydrogen atoms are substituted by the above “halogen". Specific examples thereof include fluoromethyl, chloromethyl, fluoroethyl, difluoromethyl, dichloromethyl, difluoroethyl (e.g., 2,2-difluoroethyl), trifluoromethyl, trichloromethyl, trifluoroethyl (e.g., 2,2,2-trifluoroethyl), and the like.
• Alkoxy as used herein includes, for example, a straight or branched alkoxy having 1 to 8 carbon atoms (C 1 -C 8 ), preferably 1 to 6 carbon atoms (C 1 -C 6 ). Specific examples thereof include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, n-heptyloxy, n-octyloxy, and the like.
• Cycloalkyl as used herein includes, for example, monocyclic, bicyclic or tricyclic saturated hydrocarbon group having 3 to 10 carbon atoms (C 3 -C 10 ). Specific examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.1.0]pentyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl and bicyclo[3.2.1]octyl, adamantyl (also called tricyclo[3.3.1.1 3.7 ]decanyl), and the like.
• Halocycloalkyl as used herein includes, for example, the above “cycloalkyl” wherein 1 to 3 hydrogen atoms are substituted by the above "halogen". Specific examples thereof include 2-fluorocyclopropyl. 3,3-difluorocyclobutyl, 2,2-difluorocyclopentyl, 4,4-difluorocyclohexyl, and the like.
• Cycloalkenyl as used herein includes, for example, a monocyclic, bicyclic or tricyclic, unsaturated hydrocarbon group having 3 to 10 carbon atoms (C 3 -C 10 ) and 1 or 2 double bonds in the molecule. Specific examples thereof include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like.
• Heterocycloalkyl as used herein includes, for example, a monocyclic or bicyclic saturated heterocyclic ring having 1 to 4 heteroatoms selected from nitrogen atom, sulfur atom, and oxygen atom in the ring and being composed of 4 to 10 ring-constituting atoms. Specific examples thereof include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, 1,3-dioxolanyl, 1,4-dioxolanyl, tetrahydrothiophenyl, and the like.
• Aryl as used herein includes, for example, a monocyclic, bicyclic or tricyclic, aromatic hydrocarbon group having 6 to 14 carbon atoms. Specific examples thereof include phenyl, 1-naphthyl, 2-naphthyl. 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl, 10-phenanthryl, and the like. Particularly, phenyl is preferable.
• Heteroaryl as used herein includes, for example, a monocyclic or bicyclic aromatic heterocyclic ring having 1 to 4 heteroatoms selected from nitrogen atom, sulfur atom, and oxygen atom in the ring and being composed of 5 to 10 ring-constituting atoms.
• furyl e.g., 2-furyl, 3-furyl
• thienyl e.g., 2-thienyl, 3-thienyl
• pyrrolyl e.g., 2-pyrrolyl, 3-pyrrolyl
• imidazolyl e.g., 2-imidazolyl, 4-imidazolyl
• pyrazolyl e.g., 3-pyrazolyl, 4-pyrazolyl
• triazolyl e.g., 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,2,3-triazol-4-yl
• tetrazolyl e.g., 5-tetrazolyl
• oxazolyl e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl
• isoxazolyl e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazoly
• furyl e.g., 2-furyl, 3-furyl
• imidazolyl e.g., 2-imidazolyl, 4-imidazolyl
• thiazolyl e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl
• pyridyl e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl
• pyridazinyl e.g., 3-pyridazinyl, 4-pyridazinyl
• pyrimidinyl e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl
• Carbon ring refers to a cyclic structure composed of carbon atoms, and examples thereof include the above “cycloalkyl”, “cycloalkenyl”, and “aryl”.
• Heterocyclic ring refers to, for example, a cyclic structure composed of carbon atoms and one or more heteroatoms selected from nitrogen atom, sulfur atom, and oxygen atom, and examples thereof include the above “heterocycloalkyl” and “heteroaryl”.
• 3- to 8-Membered saturated or unsaturated monocyclic nitrogen-containing heterocyclic ring refers to, for example, saturated or unsaturated monocyclic heterocyclic ring having 1 to 4 nitrogen atoms in the ring and being composed of 3 to 8 ring-constituing atoms.
• pyrrolyl e.g., 2-pyrrolyl, 3-pyrrolyl
• imidazolyl e.g., 2-imidazolyl, 4-imidazolyl
• pyrazolyl e.g., 3-pyrazolyl, 4-pyrazolyl
• triazolyl e.g., 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,2,3-triazol-4-yl
• tetrazolyl e.g., 5-tetrazolyl
• pyridyl e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl
• 1,2,3,6-tetrahydropyridyl pyridazinyl (e.g., 3-pyr
• 5- to 10-Membered, monocyclic or bicyclic saturated heterocyclic ring refers to, for example, monocyclic or bicyclic saturated heterocyclic ring having 1 to 4 heteroatoms selected from nitrogen atom, sulfur atom, and oxygen atom in the ring and being composed of 5 to 10 ring-constituting atoms.
• azetidinyl pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, 1,3-dioxolanyl, 1,4-dioxolanyl, tetrahydrothiophenyl, and the like.
• Cyano refers to a group represented by -CN.
• Hydrox refers to a group represented by -OH.
• Optionally-substituted means that a specified group may or may not be substituted, i.e., it may be optionally substituted or unsubstituted.
• optionally-substituted alkyl refers to both a substituted alkyl or an unsubstituted alkyl.
• Examples of a substituent that substitutes a specified group include the above-defined alkyl, haloalkyl, alkoxy, cycloalkyl, halocycloalkyl, heterocycloalkyl, halogen, cyano, oxo, hydroxy, amino, aryl, heteroaryl, and the like, and combined substituents of these substituents (for example, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, amino, aryl, heteroaryl, and the like, which is substituted by at least one substituent selected from the group consisting of alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocycloalkyl, halogen, cyano, oxo, hydroxy, amino, aryl and heteroaryl).
• the number of substituents for a specified group is, for example, 1 to 3, preferably 1 or 2, more preferably 1.
• A is preferably wherein
• A is more preferably wherein
• B is preferably optionally-substituted, 4- to 6-membered saturated or unsaturated monocyclic nitrogen-containing heterocyclic ring, and more preferably azetidinyl, piperidinyl or 1,2,3,6-tetrahydropyridyl, particularly preferably azetidinyl, which may be optionally substituted by C 1 -C 6 alkyl (e.g., methyl).
• R 4 is preferably -CONR 8 R 9 , wherein R 8 and R 9 are each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 6 cycloalkenyl, heterocycloalkyl, aryl, and heteroaryl, each of which may be optionally substituted; or R 8 and R 9 , together with the atom to which they are attached, form optionally-substituted, 5- to 10-membered monocyclic or bicyclic saturated heterocyclic ring or 5- to 10-membered monocyclic or bicyclic unsaturated heterocyclic ring.
• compound A-1 which is commercially available or synthesized by a known method
• compound B-1 which is commercially available or synthesized by a known method
• LDA lithium diisopropylamide
• a solvent such as THF or diethyl ether
• LDA may be commercially available or prepared from diisopropylamine and n-butyl lithium (n-BuLi).
• This step is the oxidation of the hydroxyl group of compound C-1 to afford D-1.
• This reaction is carried out using 2-azadamantane-N-oxyl (AZADOL Registered Trademark), 2,2,6,6-tetramethylpiperidine-1-oxyl radical (TEMPO), Dess-Martin reagent, etc., in a solvent such as dichloromethane or dichloroethane at 0°C to room temperature for 30 minutes to 24 hours, preferably 30 minutes to 6 hours, more preferably 30 minutes to 3 hours to afford compound D-1.
• a solvent such as dichloromethane or dichloroethane at 0°C to room temperature for 30 minutes to 24 hours, preferably 30 minutes to 6 hours, more preferably 30 minutes to 3 hours to afford compound D-1.
• compound D-1 is reacted in the presence of hydrazine monohydrate in a solvent such as dioxane, THF, etc., at room temperature to reflux temperature, preferably in dioxane at 100°C for 1 hour to 48 hours, preferably 8 hours to 24 hours to afford compound Ea-1.
• a solvent such as dioxane, THF, etc.
• This step is the alkylation of compound Ea-1 with an alkylating agent F-1 in the presence of a base to afford compound G-1, which can be performed according to a known method for alkylation reaction.
• the reaction of compound Ea-1 with an alkylating agent F-1 is carried out in the presence of a base such as sodium hydride, potassium hydride, potassium carbonate, sodium carbonate, cesium carbonate, etc., in a solvent such as dimethylformamide, tetrahydrofuran, etc., at 0°C to 120°C, preferably at room temperature to 120°C, for 1 to 48 hours, preferably 1 to 12 hours.
• a base such as sodium hydride, potassium hydride, potassium carbonate, sodium carbonate, cesium carbonate, etc.
• a solvent such as dimethylformamide, tetrahydrofuran, etc.
• A, R 1 , R 2 , R 3 , R 4 , B, X 1 , and PG 1 are as defined above.
• X 3 represents I, Cl, or Br.
• This process is the halogenation of compound H-1, which is commercially available or synthesized by a known method, to afford compound J-1.
• Halogenation can be performed by reactions normally used for halogenation of aromatic rings.
• Compound H-1 is reacted with chlorine, bromine, iodine, N-chlorosuccinimide (NCS), and N-bromosuccinimide (NBS) in a solvent such as dichloromethane, dichloroethane, carbon tetrachloride, DMF, etc., at 0°C to room temperature for 30 minutes to 48 hours, preferably 1 hour to 12 hours, to afford compound J-1.
• compound J-1 is alkylated with an alkylating agent F-1 in the presence of a base to afford compound K-1.
• Compound K-1 can be prepared by conducting the reaction under the same conditions as Step 4 in the synthesis of compound (G-1) above.
• This process is the Negishi coupling reaction of compound K-1 with compound L-1 to afford compound G-2.
• a palladium catalyst such as tetrakistriphenylphosphine palladium (hereinafter referred to as "Pd(PPh 3 ) 4 "), palladium(II) acetate (hereinafter referred to as “Pd(OAc) 2 "), bis(triphenylphosphine)palladium(II) dichloride (“Pd(PPh 3 ) 2 Cl 2 "), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) ⁇ dichloromethane adduct (“Pd(dppf) 2 Cl 2 "), etc., and compound L-1, which is commercially available or synthesized by a known method, and the mixture is reacted under a nitrogen atmosphere or argon atmosphere at 0°C to 150°C, preferably 60°C to
• This step is the deprotection of the protecting group of compound G-2 to afford compound M-1, and can be performed with reference to Wuts and Greene, “Greene's Protective Groups in Organic Synthesis", 4th edition, John Wiley & Sons Inc., 2006 , or P.J. Kocienski, "Protecting Groups", 3rd edition, Thimeme, 2005 .
• the reactive compound of compound N-1 includes, for example, an acid halide (e.g., acid chloride, acid bromide), mixed acid anhydride, imidazolide, active amide, or other compounds normally used in amide condensation reactions.
• an acid halide e.g., acid chloride, acid bromide
• mixed acid anhydride e.g., imidazolide, active amide, or other compounds normally used in amide condensation reactions.
• R A represents methyl, ethyl, n-propyl, or t-butyl.
• This step is the deprotection of the protecting group of compound G-2 to afford compound M-2, and can be performed with reference to Wuts and Greene, “Greene's Protective Groups in Organic Synthesis", 4th edition, John Wiley & Sons Inc., 2006 , or P.J. Kocienski, "Protecting Groups", 3rd edition. Thimeme, 2005 .
• This step is the condensation of compound M-2 with compound N-1 or its reactive compound in the presence of a condensing agent to afford compound O-2. It can be carried out by the same method as Step 2 in the synthesis of compound (I) above.
• This step is the deprotection of the protecting group (PG 2 ) of compound O-2 to afford compound P-2, and can be performed with reference to Wuts and Greene, “Greene's Protective Groups in Organic Synthesis", 4th edition, John Wiley & Sons Inc., 2006 , or P.J. Kocienski, "Protecting Groups", 3rd edition, Thimeme, 2005 .
• This step is the condensation of compound Q-1 with compound P-2 or its reactive compound in the presence of a condensing agent to afford compound 1-2. It can be carried out by the same method as Step 2 in the synthesis of compound (I) above.
• Step 1-Step 2 and Step 3-Step 4 can be switched to afford compound I-2. That is, the carboxylic acid obtained by deprotection (hydrolysis) of R A of compound G-2 is condensed with compound Q-1. Then, the amine obtained by deprotection of PG 1 can be condensed with compound N-1 to afford compound I-2.
• stereo isomers can be prepared, for example, by means of optical resolution from the racemate thereof according to a known method using an optically active acid (e.g., tartaric acid, dibenzoyltartaric acid, mandelic acid, 10-camphor sulfonic acid, etc.), utilizing its basicity, or by using an optically active compound prepared in advance as a starting material.
• an optically active acid e.g., tartaric acid, dibenzoyltartaric acid, mandelic acid, 10-camphor sulfonic acid, etc.
• the stereo isomers may be prepared by optical resolution using a chiral column or by asymmetric synthesis.
• the compound of the present invention has a DDR1 kinase inhibitory activity, as shown in Test Examples below.
• one embodiment of the present invention provides the compound of the present invention for use in inhibiting a DDR1 kinase.
• one embodiment of the present invention provides a method for preventing or treating a disease in which a DDR1 kinase is involved, which comprises administering the compound of the present invention to a subject in need thereof.
• one embodiment of the present invention provides the use of the compound of the present invention for the manufacture of a prophylactic agent or therapeutic agent for a disease in which a DDR1 kinase is involved.
• Diseases to which the compound of the present invention can be applied include, for example, Alport syndrome, IgA nephropathy, Goodpasture syndrome, anti-glomerular basement membrane nephritis, lupus nephritis, ANCA-related nephritis, diabetic nephropathy, purpura nephritis, focal segmental glomerulosclerosis, chronic kidney failure, minimal change nephrotic syndrome, mesangial proliferative glomerulonephritis, membranoproliferative glomerulonephritis, crescentic glomerulonephritis, membranous nephropathy, pulmonary fibrosis, myelofibrosis, liver fibrosis, acute myeloid leukemia, chronic myelogenous leukemia, acute lymphoid leukemia, chronic lymphocytic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, gli
• one embodiment of the present invention provides a prophylactic agent or therapeutic agent for the above diseases, comprising the compound of the present invention.
• one embodiment of the present invention provides a method for preventing or treating the above diseases, which comprises administering the compound of the present invention to a subject in need thereof.
• one embodiment of the present invention provides the use of the compound of the present invention for the manufacture of a prophylactic agent or therapeutic agent for the above diseases.
• Subject refers to a human or non-human animal that has or is suspected to have a disease in which DDR1 is involved. In one embodiment of the present invention, the subject is mammal. In one embodiment of the present invention, the subject is human.
• the compound of the present invention can be used for a therapeutic agent for various diseases as mentioned above in a mammal such as human, mouse, rat, rabbit, dog, cat, cow, horse, pig, monkey, etc., as it is or as a pharmaceutical composition containing the compound in an amount, e.g., 0.001% to 99.5%, preferably 0.1% to 90%, in a pharmaceutically acceptable carrier, etc.
• the carrier may be one or more of the customary solid, semi-solid or liquid diluents, fillers and other excipients used for formulation.
• the pharmaceutical composition according to the present invention is preferably administered in a unit dosage form.
• the pharmaceutical composition can be administered via intra-tissue, oral, intravenous, topical (transdermal, eye drops, intraperitoneal, intrathoracic, etc.) or rectal route.
• the pharmaceutical composition is administered in a dosage form suitable for the mode of administration.
• the dose as a pharmaceutical is preferably adjusted taking into consideration the conditions such as age, weight, type and severity of disease of a patient, administration route, type of the compound of the invention, whether or not it is a salt, and the type of the salt.
• the effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof for an adult, in the case of oral administration is preferably within a range of 0.01 mg to 5 g/day, preferably 1 mg to 500 mg/day. In some cases, a smaller amount may be sufficient or a larger amount may be required.
• the dosage can be administered once a day or can be divided and administered several times a day, or in the case of intravenous administration, the dosage can be administered rapidly or sustainably within 24 hours.
• ACE inhibitors angiotensin-converting enzyme inhibitors
• ARBs angiotensin II AT1 receptor blockers
• ARBs include candesartan, losartan, valsartan, olmesartan, azilsartan, irbesartan, telmisartan, and the like.
• ACE inhibitors include ramipril, lisinopril, enalapril, imidapril, trandolapril, and the like.
• One or more hydrogen, carbon and/or other atoms in the compound of the present invention may be replaced with an isotope thereof.
• isotopes include 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, 123 I and 33 Cl, i.e., hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine.
• the compound substituted with such an isotope may be useful as a pharmaceutical and includes all radiolabeled compounds of the compound of present invention.
• the compound of the present invention can be prepared from a known compound per se or an intermediate easily preparable from a known compound, according to the following methods, Examples described below or known methods.
• the solvents, reagents and starting materials used in each step of the following processes are commercially available, such commercially available products can be used as they are.
• the compounds obtained and the starting materials used in each step of the following processes may form a salt and can be converted by a well-known method into another type of salt or a free form.
• the compound obtained or the starting material used in each step in the following processes is a free form. it can be converted into a desired salt by a known method. Examples of such salts include those similar to the salts as described for the compound of the present invention.
• a protecting group may be introduced in these substituents by a known method in advance, and the target compound can be obtained by removing the protecting group after the reaction if necessary.
• protecting groups can be found, for example, in Wuts and Greene, “Greene's Protective Groups in Organic Synthesis", 4th edition, John Wiley & Sons Inc., 2006 , or P.J. Kocienski, "Protecting Groups", 3rd edition, Thimeme, 2005 , and may be selected as appropriate according to the reaction conditions.
• the compound obtained in each step of the following processes can be isolated or purified according to a conventional method such as solvent extraction, concentration, distillation, sublimation, recrystallization, reprecipitation, chromatography, and the like.
• the compound may be used in the next step as a reaction mixture or a crude product.
• MS was performed using LCMS.
• ESI was used as a method for ionization. Observed values of the mass spectrometry are expressed as m/z.
• Initiator 60 (Biotage) was used, which can achieve a temperature of 40 to 250°C and a pressure of up to 20 bar.
• a reaction vessel containing zinc (3.62 g) was heated with a heat gun under reduced pressure for 3 minutes and replaced with argon. After bringing the reaction vessel to room temperature, DMA (40 mL) was added and degassed with argon. After that, to the mixture were added 1,2-dibromoethane (0.341 mL) and chloro(trimethyl)silane (0.602 mL) and then the mixture was stirred at room temperature for 15 minutes. A solution of tert-butyl 3-iodoazetidine-1-carboxylate (11.2 g) in DMA (40 mL) was added dropwise to the mixture through a dropping funnel. The mixture was stirred at room temperature for 1 hour to afford a solution of [1-(tert-butoxycarbonyl)azetidin-3-yl]zinc(II) iodide in DMA.
• a reaction vessel containing diethyl ether (30 mL) was cooled on ice, and 60% sodium hydride (596 mg) was added thereto. Ethanol (0.087 mL) was then added thereto, and then the mixture was stirred for 20 minutes under an ice bath condition.
• a solution of 4,4-difluorocyclohexan-1-one (2.0 g) and ethyl formate (1.80 mL) in diethyl ether (10 mL) was added dropwise through a dropping funnel over 10 minutes. The mixture was gradually brought to room temperature and stirred overnight. Then ethanol (0.3 mL) was added to the reaction solution, and then the mixture was stirred at room temperature for 1 hour.
• tert-butyl 2-bromo-5-fluoropyridine-4-carboxylate for example, synthesized according to a method described in WO202186879 ) (2.00 g
• tert-butyl carbonate (1.02 g)
• Xantphos 168 mg
• cesium carbonate 3.30 g
• 1,4-dioxane 24 mL
• Pd(OAc) 2 33 mg
• the insoluble material was filtered off with Celite ® , and the mother liquor was washed sequentially with water and a saturated saline solution, then dried over anhydrous magnesium sulfate.
• the solvent was removed under reduced pressure to afford tert-butyl 2- ⁇ [(tert-butoxy)carbonyl]amino ⁇ -5-fluoropyridine-4-carboxylate.
• Compound RE-29 was prepared according to the same synthetic route as described for Compound RE-28, using 4,4-difluorocyclohexane-1-amine hydrochloride.
• 1 H-NMR 400 MHz, DMSO-d6) ⁇ 8.09 (d, 1H), 6.99 (s, 1H), 6.86-6.83 (m, 2H), 3.95 (brs, 1H), 2.06-1.92 (m, 6H), 1.60-1.51 (m, 2H)
• Compound RE-30 was prepared starting from Intermediate RE-30B. according to procedures similar to those described in Steps 3 through 7 of Reference Example 1 for the preparation of Compound RE-1. MS(m/z):347.0[M+H] +
• Compound RE-31 was prepared starting from Intermediate RE-31A, according to procedures similar to those described in Steps 5 through 7 of Reference Example 1 for the preparation of Compound RE-1. MS(m/z): 349.0 [M+H] +
• Compound RE-34 was prepared starting from Intermediate RE-34B, according to procedures similar to those described in Steps 1 to 2 of Reference Example 33 for the preparation of Compound RE-33. MS(m/z):454.3[M+H] +
• tert-butyl 3-[1-(2-ethoxy-2-oxoethyl)-5-methyl-1H-indazol-3-yl]azetidine-1-carboxylate To a mixture of the resulting tert-butyl 3-[1-(2-ethoxy-2-oxoethyl)-5-methyl-1H-indazol-3-yl]azetidine-1-carboxylate (467 mg), methanol (2 mL) and THF (2 mL) was added 2 M aqueous sodium hydroxide solution (1.9 mL) at room temperature, and then the mixture was stirred overnight.
• Compound RE-54 was prepared starting from Intermediate RE-2C, according to procedures similar to those described in Steps 4 through 6 of Reference Example 2 for the preparation of Intermediate RE-2F, using ethyl bromofluoroacetate instead of ethyl 2-bromoacetate. MS (m/z): 529.2 [M+Na] +
• Compound RE-62 was prepared starting from Intermediate RE-2E, according to procedures similar to those described in Steps 1 to 2 of Reference Example 51 for the preparation of Compound RE-51. MS(m/z): 363.1 [M+H] +
• Compound RE-63 was prepared starting from Intermediate RE-4C, according to procedures similar to those described in Steps 1 to 2 of Reference Example 61, for the preparation of Compound RE-61, using 2-methylpropan-2-amine instead of (2R)-2-(trifluoromethyl)morpholine hydrochloride. MS (m/z): 287.2 [M+H] +
• Compound RE-64 was prepared starting from Intermediate RE-4C, according to procedures similar to those described in Steps 1 to 2 of Reference Example 51 for the preparation of Compound RE-51, using diisopropylamine instead of 2,2,2-trifluoro-N-methylethanamine hydrochloride. MS (m/z): 315.3 [M+H] +
• Compound RE-65 was prepared starting from Intermediate RE-4C, according to procedures similar to those described in Steps 1 to 2 of Reference Example 51 for the preparation of Compound RE-51, using N,2-dimethylpropan-2-amine instead of 2,2,2-trifluoro-N-methylethanamine hydrochloride. MS(m/z): 301.2 [M+H] +
• Compound RE-69 was prepared starting from Intermediate RE-6C, according to procedures similar to those described in Steps 1 to 2 of Reference Example 66 for the preparation of Compound RE-66, using (2S)-2-(trifluoromethyl)pyrrolidine hydrochloride instead of 2,2,2-trifluoro-N-methylethaneamine hydrochloride. MS (m/z): 371.3 [M+H] +
• Compound RE-75 was prepared starting from Intermediate RE-11A, according to procedures similar to those described in Steps 3 through 5 of Reference Example 11 for the preparation of Intermediate RE-11E. MS (m/z): 396.2 [M-Boc+2H] +
• Compound RE-76 was prepared starting from Intermediate RE-11B, according to procedures similar to those described in Steps 3 through 5 of Reference Example 11 for the preparation of Intermediate RE-11E, using (2R)-2-(trifluoromethyl)morpholine hydrochloride instead of (2S)-2-(trifluoromethyl)pyrrolidine hydrochloride. MS (m/z): 536.2 [M+Na] +
• Compound RE-77 was prepared starting from Intermediate RE-11B, according to procedures similar to those described in Steps 3 through 5 of Reference Example 11 for the preparation of Intermediate RE-11E, using (2S)-2-(trifluoromethyl)morpholine hydrochloride instead of (2S)-2-(trifluoromethyl)pyrrolidine hydrochloride. MS (m/z): 536.2 [M+Na] +
• Compound RE-88A was prepared starting from Intermediate RE-17B, according to procedures similar to those described in Steps 4 to 5 of Reference Example 15 for the preparation of Intermediate RE-15E. MS(m/z): 346.2 [M+H] +

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